Effect of the Ergot Derivative Lisuride Hydrogen Maleate on Serum Prolactin Concentrations in Female Rats K.-J. GRAF, F. NEUMANN, AND R. HOROWSKI Department of Endocrine Pharmacology and Department of Neuropsychopharmacology, Research Laboratories of Schering AG, Berlin and Bergkamen, West Germany rats primed with E2. The effects of R, E2, and LHM are described in relation to their mode of action within the hypothalamic-hypophyseal system which regulates PRL secretion. While the increase in serum PRL induced by R seems to be directly relatable to its known catecholamine depletion, the circadian rhythm of PRL secretion induced by E2 seems to be influenced or mediated by central neural mechanisms.
ABSTRACT. The influence of a new synthetic ergot derivative, lisuride hydrogen maleate (LHM) on serum prolactin (PRL) concentrations was investigated in female rats using different test models: 1. in reserpine (R)-pretreated intact females, and 2. in ovariectomized (OVX) estradiol benzoate (E2)primed animals with or without an additional pretreatment with R. In all the models used LHM was strongly effective in lowering serum PRL. Doses from 0.025 to 0.5 mg/kg LHM, given orally as well as subcutaneously, suppressed serum PRL. Depending
The effects of LHM on serum PRL in these test
on the dose used, the serum PRL was lowered to a different extent for up to 12 h. LHM was at least as effective as the well-known potent inhibitor of PRL secretion CB-154 in lowering serum PRL in OVX
models can be related to its dopaminergic action and constitute further evidence for the central functions of dopaminergic mechanisms in the regulation of PRL secretion. (Endocrinology 98: 598, 1976)
I
N ANIMALS and in man neurotransmitters are implicated in the regulation of gonadotrophin secretion. Of special interest are the dopaminergic mechanisms which exert an inhibitory control on prolactin (PRL) secretion (for reviews, see 1,2). It has been thought that dopamine (DA) stimulates the synthesis or the release of a prolactin-release inhibiting factor (PIF) (2-5) or may even be PIF itself (6-8). In spite of numerous in vivo and in vitro investigations this is still controversial. It is also not known whether the inhibitory effect of the dopaminergic mechanism takes place at the hypothalamus and/or at the level of the anterior pituitary (AP). In this context, several substances which are known or supposed to act on dopaminergic systems were tested for their influence on PRL secretion. Besides L-dopaandapomorphine, which are well-known dopamine agonists, ergot derivatives have proved to be the most effective in suppressing PRL secretion in animals and in man.
It is tempting to speculate that ergot compounds, too, inhibit PRL secretion via a dopaminergic mechanism. This hypothesis is further supported by recently published data which indicate that ergotoxine derivatives, such as ergocornine and 2-Br-ergocryptine (CB-154), stimulate dopaminergic receptors (5,9,10). Against this background, the effect of lisuride hydrogen maleate (LHM), an isoergolene derivative with strong peripheral anti-serotoninergic (11) and central dopaminergic1 activities, was investigated with respect to its potency in inhibiting PRL secretion. This work was undertaken to determine the effectiveness of LHM in lowering serum PRL concentrations in comparison with the known highly potent PRL inhibitor CB-154, an ergotoxine derivative. To acquire further information about the mode of action of these compounds, we tested them in two different test models, using reserpine and/or estradiol 1
Received June 10, 1975.
Horowski, R., and H. Wachtel, Eur J Pharmacol (In press).
598
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LHM, A PROLACTIN INHIBITOR IN FEMALE RATS
benzoate (E2) which show different interactions (12) within the central mechanisms regulating PRL secretion. Materials and Methods Mature female rats of the Wistar strain, weighing 180-200 g, receiving a standard diet and water ad libitum, were used in these studies. The influence of LHM (Lysenyl Spofa, N-(D-6methyl-8-isoergolenyl-N',N'-diethylcarbamide hydrogen maleate) on PRL secretion, measured by radioimmunoassay of serum PRL, was investigated in two different models: a) in reserpinetreated intact females and b) in ovariectomized (OVX) estrogen-primed females with or without an additional pretreatment with reserpine. Reserpine model Intact female rats in different stages of the estrous cycle were pretreated with reserpine given ip as a single injection of 2 mg/kg at 9, 10, or 11 AM on day 1, that is, 21-23 h prior to the injection of LHM on day 2. Exp 1 Various doses of LHM (0.025, 0.05, 0.1, and 0.2 mg/kg were injected SC at 9 AM into intact female rats pretreated 23 h earlier with reserpine. Serum PRL was determined 1 and 6 h later (at 10 AM and 3 PM). Exp 2 The time relationship between a single injection of LHM (0.1 mg/kg SC) and serum PRL levels was investigated. LHM was injected once at 8 AM into intact female rats pretreated with reserpine and the serum PRL was determined at intervals for up to 24 h. Exp 3 Various doses of LHM (0.025, 0.1, and 0.4 mg/kg) were given orally (po) to intact female rats pretreated with reserpine. Serum PRL was determined after 3, 9, and 12 h (at 11 AM, 5 PM, and 8 PM).
599
ovariectomy at 3 PM (indicated as day 1 of the experiment). The following day (day 2) at 2 PM one group of OVX rats received in addition a single injection of reseipine (2 mg/kg ip) whereas the other group received no further treatment. Exp 4 OVX rats, primed with E2, received a single injection of either LHM (0.5 mg/kg SC) or CB-154 (2 mg/kg SC) at 8 AM on day 3. Serum PRL was estimated after 9 and 33 h (at 5 pm on day 3 and day 4). Exp 5 The time relationship between a single injection of either LHM (0.5 mg/kg SC) or CB-154 (2 mg/kg SC) and serum PRL concentrations was investigated in OVX rats pretreated with E 2 and reserpine. LHM or CB-154 was injected once at 8 AM on day 3, and serum PRL was determined at intervals of up to 12 h (see also under Results). General experimental procedures E2 was dissolved in sesame oil. Reserpine was used as a suspension of the hydrochloride stabilized by a 0.085 (wt/vol)% solution of Myrj 53 (polyoxyethylene-stearate, Atlas-Chemie, Essen) in 0.9 (wt/vol)% NaCl. LHM and CB-154 were dissolved in 0.9 (wt/vol)% NaCl. Rats were killed by decapitation, and blood from the trunk was collected in centrifuge tubes, allowed to clot at 4 C, and centrifuged at 3000 x g for 10 minutes. The serum was removed and stored at —20 C until assayed. PRL was estimated using the radioimmunoassay kit supplied by the Rat Pituitary Hormone Distribution Program of the National Institute of Arthritis, Metabolism, and Digestive Diseases (NIAMDD). The assay procedures, using a double-antibody radioimmunoassay, were those recommended by the NIAMDD. The results are expressed in terms of the rat PRL reference standard (NIAMDD-RatProlactin-RP-1) in ng/ml as the mean (±SEM) of all samples in each group of animals.
Results
Estrogen model
Reserpine model
Mature female OVX rats were primed with a single injection of 25 /ug/kg E2 SC on day 12 after
A single igle injection injection ot of reserpine reserpine into into temale female cvcle rats inn different stages of the estrous cycle
IJ V I %>\S II %/\J\A/\S
1/
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Endo • 1976 Vol 98 • No 3
GRAF, NEUMANN AND HOROWSKI
600
led to a long-lasting increase of serum PRL levels during the following day without any significant diurnal variations. PRL reached maximum levels of 231 ± 55 ng/ml about 32 h after reserpine was injected (Fig. 1). In contrast, in OVX rats, a single injection of reserpine led to wide fluctuations in serum PRL throughout the day. There were no obvious time relationships between the reserpine and serum PRL concentrations or between the latter and the time of the day (Fig. 1). Exp 1 LHM lowered the elevated serum PRL levels in reserpine pretreated intact female rats (Fig. 2). All doses of LHM used were maximally effective when the levels were measured 1 h after the injection of the test substance; however, 6 h after the injection, the effect of LHM was somewhat smaller and the degree of inhibition was dosedependent.
•
rngi
Exp 2 The time course of the serum PRLlowering action of a single dose of LHM (0.1 mg/kg SC) in intact female rats pretreated with reserpine is presented in Fig. 3. It can be seen that the effect of LHM at this dose lasted up to 9 h after injection, and that by 11 h after injection the effect had vanished (see also Figs. 2, 4, and 7). Exp 3 Figure 4 shows the oral effectiveness of LHM in lowering serum PRL levels in intact female rats pretreated with reserpine. All doses tested were effective. The dose of 0.025 mg/kg was slightly less effective than 0.1 and 0.4 mg/kg, especially with respect to the duration of action, but with all doses the lowering effect lasted for at least 12 h. During this time 0.1 and 0.4 mg/kg LHM remained maximally effective, whereas the lowest dose of 0.025 mg/kg tended to be less effective with increasing time. When ( ) No of animals/group
NIAMD- RAT -PROLACTIN RP 1
Lm7.
I
M ±SE M 9 + R
500-
V + R 9 Controls
400(7)
300200-
\i2 mg/kg
\
(7)
J(5)
5 p.m.
7 p.m.
8 a.m.
Time of day
3
Day of experiment
1
100-
r 9a .m. 1
(4)
s'
9 a.m.
11 a.m.
2
FIG. 1. Time relationship between a single ip injection of reserpine (R) and serum prolactin concentrations in intact female rats and in ovariectomized rats.
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601
LHM, A PROLACTIN INHIBITOR IN FEMALE RATS
•
— ml
1 after injection of LHM
500-
FlC. 2. The influence of various doses of lisuride hydrogen maleate (LHM), given subcutaneously, on serum prolactin concentrations in intact female rats pretreated with 2 mg/kg reserpine ip at 10 AM (i.e., 23 h prior to the injection of LHM).
NIAMD • RAT • PROLACTIN
( ) No of animals/group IMtSEM
RP - 1
jijijgjj 6 n after injection of LHM (5)
I
400300200-
(6)
(6) (6)
100(6)
(6)
Con- 0.025 trol
*
(5)
(6)
(6)
ii m
0.05 ' 0.1 ' 0.2 ' Con-' 0.025' 0.05 ' 0.1 trol
the effectiveness of the same dose (0.1 mg/kg) was compared according to different routes of administration, it was found that oral administration was at least as effective as subcutaneous injection. Estrogen model
0.2 ' rmg-i Lkg J
jection of reserpine (2 mg/kg, ip) into OVX rats primed with 25 /xg/kg SC E2 resulted in elevated PRL concentrations throughout the following day without any significant diurnal fluctuations (Fig. 5; cf., Fig. 1). Exp 4
A single injection of 25 /Ag/kg SC E2 into mature OVX rats induced a rhythmic release of PRL as measured by serum PRL levels on day 3, where day 1 is the day when E2 was injected (Fig. 5). A dramatic surge of PRL was found during the afternoon of day 3 between 3 and 9 PM with a peak concentration at about 5 PM, whereas during the morning and night of day 3, basal serum PRL levels were found. In contrast, an in-
LsnJ
NIAMD
The serum PRL peak in the afternoon 2 days later induced by E2 in OVX rats could be inhibited completely by both 0.5 mg/kg SC LHM and by 2 mg/kg SC CB-154 (Fig. 6), when given 9 h before the peak was expected. It will be noted that an afternoon PRL surge occurred one day later (at 5 PM on day 4 of the experiment), also induced by the single injection of E2 on day 1 of the experiment. Neither the single dose of LHM ( ) I
RAT - PROLACTIN - RP 1
No of animals/group MtSEM LHM 0.1 mg/kg sc
500-
Controls
FIG. 3. Time relationship between a single injection of lisuride hydrogen maleate (LHM) and senim prolactin concentrations in intact female rats pretreated with 2 mg/kg reserpine (R) ip.
400300LHM 200100-
9 a.m.
8 a.m.
9 a.m.
11 a.m.
5 p.m.
7 p.m.
8 a.m.
Time of day Day of experiment
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GRAF, NEUMANN AND HOROWSKI
602 •
rug-i LmlJ
( ) No of animals/group T M±SE M
N I A M D - R A T - PROLACTIN - RP- 1
•
500-
400-
Controls p o LHM 0.025, 0.1. 0.4 mg/kg p o LHM 0.1 mg/kg s_c_
(8)
FIG. 4. Time relationship between various doses of lisuride hydrogen maleate (LHM), given orally at 8 AM, and serum prolactin concentrations in intact female rats pretreated with 2 mg/kg reserpine ip.
(10) 300-
200-
100-
I
1
1
1 l
(5)
l
I
(5) (5)
(9)
(4)
1 m
ABSTRACT. The influence of a new synthetic ergot derivative, lisuride hydrogen maleate (LHM) on serum prolactin (PRL) concentrations was investigated in female rats using different test models: 1. in reserpine (R)-pretreated intact females, and 2. in ovariectomized (OVX) estradiol benzoate (E2)primed animals with or without an additional pretreatment with R. In all the models used LHM was strongly effective in lowering serum PRL. Doses from 0.025 to 0.5 mg/kg LHM, given orally as well as subcutaneously, suppressed serum PRL. Depending
The effects of LHM on serum PRL in these test
on the dose used, the serum PRL was lowered to a different extent for up to 12 h. LHM was at least as effective as the well-known potent inhibitor of PRL secretion CB-154 in lowering serum PRL in OVX
models can be related to its dopaminergic action and constitute further evidence for the central functions of dopaminergic mechanisms in the regulation of PRL secretion. (Endocrinology 98: 598, 1976)
I
N ANIMALS and in man neurotransmitters are implicated in the regulation of gonadotrophin secretion. Of special interest are the dopaminergic mechanisms which exert an inhibitory control on prolactin (PRL) secretion (for reviews, see 1,2). It has been thought that dopamine (DA) stimulates the synthesis or the release of a prolactin-release inhibiting factor (PIF) (2-5) or may even be PIF itself (6-8). In spite of numerous in vivo and in vitro investigations this is still controversial. It is also not known whether the inhibitory effect of the dopaminergic mechanism takes place at the hypothalamus and/or at the level of the anterior pituitary (AP). In this context, several substances which are known or supposed to act on dopaminergic systems were tested for their influence on PRL secretion. Besides L-dopaandapomorphine, which are well-known dopamine agonists, ergot derivatives have proved to be the most effective in suppressing PRL secretion in animals and in man.
It is tempting to speculate that ergot compounds, too, inhibit PRL secretion via a dopaminergic mechanism. This hypothesis is further supported by recently published data which indicate that ergotoxine derivatives, such as ergocornine and 2-Br-ergocryptine (CB-154), stimulate dopaminergic receptors (5,9,10). Against this background, the effect of lisuride hydrogen maleate (LHM), an isoergolene derivative with strong peripheral anti-serotoninergic (11) and central dopaminergic1 activities, was investigated with respect to its potency in inhibiting PRL secretion. This work was undertaken to determine the effectiveness of LHM in lowering serum PRL concentrations in comparison with the known highly potent PRL inhibitor CB-154, an ergotoxine derivative. To acquire further information about the mode of action of these compounds, we tested them in two different test models, using reserpine and/or estradiol 1
Received June 10, 1975.
Horowski, R., and H. Wachtel, Eur J Pharmacol (In press).
598
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 01 August 2016. at 18:16 For personal use only. No other uses without permission. . All rights reserved.
LHM, A PROLACTIN INHIBITOR IN FEMALE RATS
benzoate (E2) which show different interactions (12) within the central mechanisms regulating PRL secretion. Materials and Methods Mature female rats of the Wistar strain, weighing 180-200 g, receiving a standard diet and water ad libitum, were used in these studies. The influence of LHM (Lysenyl Spofa, N-(D-6methyl-8-isoergolenyl-N',N'-diethylcarbamide hydrogen maleate) on PRL secretion, measured by radioimmunoassay of serum PRL, was investigated in two different models: a) in reserpinetreated intact females and b) in ovariectomized (OVX) estrogen-primed females with or without an additional pretreatment with reserpine. Reserpine model Intact female rats in different stages of the estrous cycle were pretreated with reserpine given ip as a single injection of 2 mg/kg at 9, 10, or 11 AM on day 1, that is, 21-23 h prior to the injection of LHM on day 2. Exp 1 Various doses of LHM (0.025, 0.05, 0.1, and 0.2 mg/kg were injected SC at 9 AM into intact female rats pretreated 23 h earlier with reserpine. Serum PRL was determined 1 and 6 h later (at 10 AM and 3 PM). Exp 2 The time relationship between a single injection of LHM (0.1 mg/kg SC) and serum PRL levels was investigated. LHM was injected once at 8 AM into intact female rats pretreated with reserpine and the serum PRL was determined at intervals for up to 24 h. Exp 3 Various doses of LHM (0.025, 0.1, and 0.4 mg/kg) were given orally (po) to intact female rats pretreated with reserpine. Serum PRL was determined after 3, 9, and 12 h (at 11 AM, 5 PM, and 8 PM).
599
ovariectomy at 3 PM (indicated as day 1 of the experiment). The following day (day 2) at 2 PM one group of OVX rats received in addition a single injection of reseipine (2 mg/kg ip) whereas the other group received no further treatment. Exp 4 OVX rats, primed with E2, received a single injection of either LHM (0.5 mg/kg SC) or CB-154 (2 mg/kg SC) at 8 AM on day 3. Serum PRL was estimated after 9 and 33 h (at 5 pm on day 3 and day 4). Exp 5 The time relationship between a single injection of either LHM (0.5 mg/kg SC) or CB-154 (2 mg/kg SC) and serum PRL concentrations was investigated in OVX rats pretreated with E 2 and reserpine. LHM or CB-154 was injected once at 8 AM on day 3, and serum PRL was determined at intervals of up to 12 h (see also under Results). General experimental procedures E2 was dissolved in sesame oil. Reserpine was used as a suspension of the hydrochloride stabilized by a 0.085 (wt/vol)% solution of Myrj 53 (polyoxyethylene-stearate, Atlas-Chemie, Essen) in 0.9 (wt/vol)% NaCl. LHM and CB-154 were dissolved in 0.9 (wt/vol)% NaCl. Rats were killed by decapitation, and blood from the trunk was collected in centrifuge tubes, allowed to clot at 4 C, and centrifuged at 3000 x g for 10 minutes. The serum was removed and stored at —20 C until assayed. PRL was estimated using the radioimmunoassay kit supplied by the Rat Pituitary Hormone Distribution Program of the National Institute of Arthritis, Metabolism, and Digestive Diseases (NIAMDD). The assay procedures, using a double-antibody radioimmunoassay, were those recommended by the NIAMDD. The results are expressed in terms of the rat PRL reference standard (NIAMDD-RatProlactin-RP-1) in ng/ml as the mean (±SEM) of all samples in each group of animals.
Results
Estrogen model
Reserpine model
Mature female OVX rats were primed with a single injection of 25 /ug/kg E2 SC on day 12 after
A single igle injection injection ot of reserpine reserpine into into temale female cvcle rats inn different stages of the estrous cycle
IJ V I %>\S II %/\J\A/\S
1/
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 01 August 2016. at 18:16 For personal use only. No other uses without permission. . All rights reserved.
Endo • 1976 Vol 98 • No 3
GRAF, NEUMANN AND HOROWSKI
600
led to a long-lasting increase of serum PRL levels during the following day without any significant diurnal variations. PRL reached maximum levels of 231 ± 55 ng/ml about 32 h after reserpine was injected (Fig. 1). In contrast, in OVX rats, a single injection of reserpine led to wide fluctuations in serum PRL throughout the day. There were no obvious time relationships between the reserpine and serum PRL concentrations or between the latter and the time of the day (Fig. 1). Exp 1 LHM lowered the elevated serum PRL levels in reserpine pretreated intact female rats (Fig. 2). All doses of LHM used were maximally effective when the levels were measured 1 h after the injection of the test substance; however, 6 h after the injection, the effect of LHM was somewhat smaller and the degree of inhibition was dosedependent.
•
rngi
Exp 2 The time course of the serum PRLlowering action of a single dose of LHM (0.1 mg/kg SC) in intact female rats pretreated with reserpine is presented in Fig. 3. It can be seen that the effect of LHM at this dose lasted up to 9 h after injection, and that by 11 h after injection the effect had vanished (see also Figs. 2, 4, and 7). Exp 3 Figure 4 shows the oral effectiveness of LHM in lowering serum PRL levels in intact female rats pretreated with reserpine. All doses tested were effective. The dose of 0.025 mg/kg was slightly less effective than 0.1 and 0.4 mg/kg, especially with respect to the duration of action, but with all doses the lowering effect lasted for at least 12 h. During this time 0.1 and 0.4 mg/kg LHM remained maximally effective, whereas the lowest dose of 0.025 mg/kg tended to be less effective with increasing time. When ( ) No of animals/group
NIAMD- RAT -PROLACTIN RP 1
Lm7.
I
M ±SE M 9 + R
500-
V + R 9 Controls
400(7)
300200-
\i2 mg/kg
\
(7)
J(5)
5 p.m.
7 p.m.
8 a.m.
Time of day
3
Day of experiment
1
100-
r 9a .m. 1
(4)
s'
9 a.m.
11 a.m.
2
FIG. 1. Time relationship between a single ip injection of reserpine (R) and serum prolactin concentrations in intact female rats and in ovariectomized rats.
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601
LHM, A PROLACTIN INHIBITOR IN FEMALE RATS
•
— ml
1 after injection of LHM
500-
FlC. 2. The influence of various doses of lisuride hydrogen maleate (LHM), given subcutaneously, on serum prolactin concentrations in intact female rats pretreated with 2 mg/kg reserpine ip at 10 AM (i.e., 23 h prior to the injection of LHM).
NIAMD • RAT • PROLACTIN
( ) No of animals/group IMtSEM
RP - 1
jijijgjj 6 n after injection of LHM (5)
I
400300200-
(6)
(6) (6)
100(6)
(6)
Con- 0.025 trol
*
(5)
(6)
(6)
ii m
0.05 ' 0.1 ' 0.2 ' Con-' 0.025' 0.05 ' 0.1 trol
the effectiveness of the same dose (0.1 mg/kg) was compared according to different routes of administration, it was found that oral administration was at least as effective as subcutaneous injection. Estrogen model
0.2 ' rmg-i Lkg J
jection of reserpine (2 mg/kg, ip) into OVX rats primed with 25 /xg/kg SC E2 resulted in elevated PRL concentrations throughout the following day without any significant diurnal fluctuations (Fig. 5; cf., Fig. 1). Exp 4
A single injection of 25 /Ag/kg SC E2 into mature OVX rats induced a rhythmic release of PRL as measured by serum PRL levels on day 3, where day 1 is the day when E2 was injected (Fig. 5). A dramatic surge of PRL was found during the afternoon of day 3 between 3 and 9 PM with a peak concentration at about 5 PM, whereas during the morning and night of day 3, basal serum PRL levels were found. In contrast, an in-
LsnJ
NIAMD
The serum PRL peak in the afternoon 2 days later induced by E2 in OVX rats could be inhibited completely by both 0.5 mg/kg SC LHM and by 2 mg/kg SC CB-154 (Fig. 6), when given 9 h before the peak was expected. It will be noted that an afternoon PRL surge occurred one day later (at 5 PM on day 4 of the experiment), also induced by the single injection of E2 on day 1 of the experiment. Neither the single dose of LHM ( ) I
RAT - PROLACTIN - RP 1
No of animals/group MtSEM LHM 0.1 mg/kg sc
500-
Controls
FIG. 3. Time relationship between a single injection of lisuride hydrogen maleate (LHM) and senim prolactin concentrations in intact female rats pretreated with 2 mg/kg reserpine (R) ip.
400300LHM 200100-
9 a.m.
8 a.m.
9 a.m.
11 a.m.
5 p.m.
7 p.m.
8 a.m.
Time of day Day of experiment
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GRAF, NEUMANN AND HOROWSKI
602 •
rug-i LmlJ
( ) No of animals/group T M±SE M
N I A M D - R A T - PROLACTIN - RP- 1
•
500-
400-
Controls p o LHM 0.025, 0.1. 0.4 mg/kg p o LHM 0.1 mg/kg s_c_
(8)
FIG. 4. Time relationship between various doses of lisuride hydrogen maleate (LHM), given orally at 8 AM, and serum prolactin concentrations in intact female rats pretreated with 2 mg/kg reserpine ip.
(10) 300-
200-
100-
I
1
1
1 l
(5)
l
I
(5) (5)
(9)
(4)
1 m
